Development and evaluation of madecassoside-loaded microemulsion for enhanced topical drug delivery

Abstract

Madecassoside, a major triterpenoid glycoside from Centella asiatica, has potential value for dermatological applications; however, its poor stratum corneum permeability is due to high hydrophilicity and large molecular size. This work focused on designing a microemulsion carrier to enhance the topical delivery of madecassoside.

Formulation regions were first screened using pseudo-ternary phase diagrams, followed by preparation of madecassoside-loaded systems with different oil phases, surfactant HLB values, cosurfactant compositions, and drug loadings. The resulting formulations were characterized for droplet size, PDI, viscosity, rat-skin permeation, skin retention, CAM irritation response, and physical stability. All prepared systems were clear and homogeneous, with droplet sizes between 28.00 ± 0.44 and 60.10 ± 0.61 nm and PDI values not exceeding 0.27 ± 0.02. Further optimization identified M10, containing IPM, Brij 30/Brij 35, Transcutol HP, and 2% madecassoside, as the most suitable formulation.

M10 produced a high 24 h cumulative permeation amount of 406.28 ± 180.73 μg/cm², corresponding to an approximately 43.2-fold increase compared with the 2% madecassoside control solution (9.41 ± 2.08 μg/cm²). In the HET-CAM assay, M10 showed an irritation score lower than the 1% SLS reference group. The formulation also remained clear after centrifugation, freeze–thaw cycling, and 30 days of storage, with no marked changes in droplet size, PDI, or viscosity. These results suggest that microemulsions are a promising strategy for enhancing topical madecassoside delivery.

Introduction

Centella asiatica is a medicinal plant widely used across China and Southeast Asia and is well known for its rich content of bioactive constituents. The major bioactive constituents are triterpenoid compounds, including asiaticoside, asiatic acid, madecassoside, and madecassic acid (Bylka et al., 2014). Among these, madecassoside has attracted considerable attention due to its diverse pharmacological activities, including anti-inflammatory (Du et al., 2014), wound-healing (Hou et al., 2016), neuroprotective (Luo et al., 2014), and anti-arthritic effects (Dou et al., 2019), as well as potential anticancer activity (Li et al., 2016b). In addition, the recent study has shown that madecassoside can suppress pro-inflammatory cytokines, including IL-23 and IL-17, regulate keratinocyte proliferation, and promote collagen synthesis, highlighting its therapeutic potential for inflammatory skin disorders such as psoriasis (OuYang et al., 2016). However, because of its high hydrophilicity and relatively large molecular size (975 g/mol), madecassoside shows limited ability to permeate through the stratum corneum, which restricts its topical application. Therefore, advanced delivery systems that can enhance madecassoside permeation are essential to improve its therapeutic potential.

Microemulsions have been widely explored as promising carriers for topical drug delivery, primarily because of their thermodynamic stability, ease of preparation, and nanoscale droplet size, which is typically below or around 100 nm. These systems consist of an oil phase, surfactant, cosurfactant, and an aqueous phase (Danielsson et al., 1981). Microemulsions can reduce interfacial tension and increase interfacial area, thereby facilitating drug transport. In addition, the presence of surfactants and cosurfactants may alter or fluidize the lipid organization of the stratum corneum, contributing to enhanced permeation (Kogan et al., 2006; Williams et al., 2004). Previous studies have demonstrated that microemulsion systems can improve the topical delivery of poorly permeable compounds (Fang et al., 2020; Peltola et al., 2003; Szumała et al., 2022). Furthermore, these systems can be optimized to balance permeation enhancement and skin tolerability, making them promising candidates for topical applications. Compared with microemulsions, nanoemulsions are kinetically stable systems and commonly require high-energy processing to produce nanoscale droplets (Jaiswal et al., 2015). Liposomes and transfersomes are vesicular carriers that can also enhance topical drug delivery, but their stability and performance may be influenced by vesicle leakage, aggregation, phospholipid oxidation, and processing conditions (Dhiman et al., 2022; Opatha et al., 2020). Therefore, because of its thermodynamic stability and relatively simple preparation, microemulsion was selected in the present study to investigate its potential to improve the skin permeation of madecassoside and to systematically evaluate the effects of oil phase, surfactant HLB, cosurfactant composition, and drug loading.

In this study, a madecassoside-loaded microemulsion was developed and optimized for topical delivery. The formulation was designed based on pseudo-ternary phase diagram construction and systematically evaluated in terms of physicochemical properties, in vitro skin permeation, irritation potential, and physical and thermodynamic stability. The aim was to identify an optimized formulation with enhanced skin permeation while maintaining acceptable skin tolerability and physicochemical stability, thereby providing a potential platform for the topical delivery of madecassoside.

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Materials

Madecassoside was obtained from TopRhyme (New Taipei, Taiwan). Peceol was supplied by Eligin Corporation (Taipei, Taiwan), and isopropyl myristate (IPM) was purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Brij 30 and Brij 35 were acquired from Acros (Belgium), while Cremophor EL was obtained from Sigma-Aldrich (NY, USA). Transcutol HP was provided by Gattefossé (Nanterre, France), and 1,5-pentanediol was sourced from Alfa Aesar (Massachusetts, USA). Azelaic acid was also obtained from Acros (Belgium). Unless otherwise specified, the chemicals and solvents employed in this study were of analytical grade.

I-Hui Chiu, Quoc Lam Vu, Pao-Chu Wu, Development and evaluation of madecassoside-loaded microemulsion for enhanced topical drug delivery, International Journal of Pharmaceutics: X, Volume 12, 2026, 100649, ISSN 2590-1567, https://doi.org/10.1016/j.ijpx.2026.100649.